Comparison of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockade for the prevention of premalignant changes in the liver

Life Sci. 2011 Aug 1;89(5-6):188-94. doi: 10.1016/j.lfs.2011.06.002. Epub 2011 Jun 15.


Aim: We investigate and compare the possible antitumor activity of clinically used angiotensin converting enzyme (ACE) inhibitors; captopril, perindopril and angiotensin II type 1 receptor (AT1R) blocker, losartan against hepatocarcinogenesis initiated by diethylnitrosoamines (DENA) and promoted by carbon tetrachloride (CCl(4)).

Main methods: Diethylnitrosamine (DENA) (200mg/kgi.p.) initiated and carbon tetrachloride (CCl(4)) (2ml/kgi.p.) promoted hepatocarcinogenesis in male Wistar rats after 8weeks.

Results: Hepatocarcinogenesis was manifested biochemically by elevation of serum hepatic tumor markers tested; α-feto protein (AFP) and carcinoembryonic antigen (CEA). In addition, hepatic carcinogenesis was further confirmed by a significant increase in hepatic tissue growth factors; vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF). Moreover a marked increase in matrix metalloproteinase-2 and hydroxyproline content were also observed. Hepatocarcinogenesis was further confirmed by a significant decrease in hepatic endostatin and metallothonein level.

Key findings: Long-term administration of the selected drugs for 2weeks before and throughout the experimental period produced a significant protection against hepatic carcinogenesis. The present results claimed that different doses of the selected drugs succeeded in normalization of serum tumor markers. Furthermore, the drugs reduced the elevated level in the hepatic growth factors, matrix metalloproteinase-2 and hydroxyproline induced by the hepatocarcinogen. Moreover, the amelioration was also accompanied by augmentation of hepatic content of metallothionein and endostatin. Histopathological examination of liver tissues of rats treated with DENA-CCl(4) correlated with the biochemical observations.

Significance: These findings suggest a similar protective effect of ACE inhibitors; captopril; perindopril and AT1R blocker, losartan against premalignant stages of liver cancer in the DENA initiated and CCl(4) promoted hepatocarcinogenesis model in rats. Therefore, RAS especially angiotensin II (Ang II) and AT1R interaction plays a pivotal role hepatocarcinogenesis development.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Anticarcinogenic Agents*
  • Captopril / pharmacology
  • Carcinoembryonic Antigen / metabolism
  • Endostatins / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblast Growth Factors / metabolism
  • Hydroxyproline / metabolism
  • Liver / pathology
  • Liver Neoplasms, Experimental / pathology
  • Liver Neoplasms, Experimental / prevention & control*
  • Losartan / pharmacology
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Metallothionein / metabolism
  • Perindopril / pharmacology
  • Precancerous Conditions / pathology
  • Precancerous Conditions / prevention & control*
  • Rats
  • Transforming Growth Factor beta1 / metabolism
  • Vascular Endothelial Growth Factor A / metabolism
  • alpha-Fetoproteins / metabolism


  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Anticarcinogenic Agents
  • Carcinoembryonic Antigen
  • Endostatins
  • Transforming Growth Factor beta1
  • Vascular Endothelial Growth Factor A
  • alpha-Fetoproteins
  • Fibroblast Growth Factors
  • Metallothionein
  • Captopril
  • Matrix Metalloproteinase 2
  • Losartan
  • Hydroxyproline
  • Perindopril